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TOWARDS AN IMPLANTABLE IPSC DERIVED TREATMENT FOR TYPE 1 DIABETES Written By: Adrien A Quant Department of Biological Sciences, <strong>Rice</strong> University BIOS 410: Stem Cell Biology Dr. Aryeh Warmflash December 15, 2022 Abstract Type 1 diabetes (T1D) is a common autoimmune disorder that progressively destroys pancreatic β-cells. Left untreated, T1D leads to progressive pancreatic destruction, hyperglycemia, vascular disease, and eventual death. Current treatments of insulin and lifestyle modification have evolved but have remained relatively unchanged for decades, requiring complex healthcare management and frequent insulin doses. While various novel treatments have been recently proposed, induced pluripotent stem cells (iPSCs) may provide a very promising, future treatment for T1D. Still under research, transplanted iPSC - derived β-cells may provide glycemic control without the immune rejection risks associated with cadaveric or ESC - derived β-cells. This review explores the current status of iPSC - derived β-cells research, the strengths and weakness of iPSC - derived β-cells, and future research directions necessary for clinical application. Towards an Implantable iPSC Derived Treatment for Type 1 Diabetes: An Introduction to Type 1 Diabetes Type 1 diabetes (T1D) is a T-cell mediated autoimmune disease that progressively destroys pancreatic β-cells, reducing insulin production and inducing life-threatening hyperglycemia (van Belle et al., 2011; Pugliese, 2013; DiMeglio, 2018). The Eisenberg Model of T1D plots decreasing β-cell mass against age, portraying a sequence of events that begins with genetic predisposition, followed by T-cell activation from a triggering environmental event, leading to progressive β- cell destruction and causing eventual T1D symptoms and death (DiMeglio, 2018). While increasing research has revealed that T1D pathogenesis is far more complicated than the Eisenberg Model suggests, the model remains relevant due to its utility in explaining the loss of β-cell mass over time. The existence of polygenic risk factors and environmental risk factors to T1D are readily apparent. Regarding genetic risk factors, T1D has an identical twin risk of 30-70%, non-twin sibling risk of 6-7%, and risk of 1-9% for children who have one parent with T1D (Redondo, 2008; Pociot, 2016). Furthermore, two HLA class 2 haplotypes, HLA DRB1*0301-DQA1*0501- DQ*B10201 (DR3) and HLA DRB1*0401- DQA1*0301-DQB1*0301 (DR4-DQ8), are collectively linked to approximately 50% of disease heritability (Noble, 2015). However, evidence of environmental factors is also readily apparent. Although T1D is traditionally considered to emerge during childhood, up to 50% of T1D cases emerge during adulthood (Thomas et al., 2018). In fact, up to 50% of adults diagnosed with type 2 diabetes (T2D) may have misdiagnosed T1D (Hope et al., 2016). Furthermore, the rates of T1D appears to be increasing across children, adolescents, and adults, which imply unknown environmental factors play a role in disease onset (DiMeglio, 2018). T1D is now understood as complex interactions between genetic, microbiome, immune, and environmental factors (DiMeglio, 2018). Despite various possible mechanisms of pathogenesis, the final T1D disease process is largely driven by T-cells. While the exact signaling mechanism is not known, autoreactive T-cells target β-cells following periods of β-cell ER stress (Engin, 2016). Since β-cell ER-stress is associated with alterations in mRNA splicing and overexpression of class 1 HLA, it is possible that the stressed β-cells are displaying novel surface antigens that upregulate the immune system (Ezerik et al., 2012). In addition, over 90% of T1D patients have serum detectable antibodies against β- cell related antigens, such as insulin, islet antigen 2, glutamate decarboxylase, zinc transporter 8, and tetraspanin-7 (McLaughlin et al., 2016). In fact, the presence of merely two serum detectable antibodies is associated with 84% risk of T1D symptoms by 18 years of age (Ziegler et al, 2013). Over time, the T-cell mediated attack leads to the progressive destruction of pancreatic β-islets, lowering insulin levels and causing the onset of T1D symptoms. In addition to chronic hyperglycemia, T1D causes various symptoms that significantly increase morbidity and mortality. As the disease progresses, the pancreas reduces in size and β- cell mass continues to decrease (Virostko et al, 2016). Left untreated, the chronic hyperglycemia leads to various microvascular-related pathologies, such as alterations in attention, visual attention, memory, retinopathy, neuropathy, nephropathy, and cardiovascular disease (Caroline, 2013). Thus, T1D can lead to significant deterioration in quality of life. Even with modern medical treatments, T1D patients can still die 8-13 years younger than people without T1D (Huo et al, 2016; Livingstone et al., 2015). 2 0 | C A T A L Y S T 2022-2023
Current Treatments for Type I Diabetes: Insulin Therapy Since glucose is necessary cellular metabolism, type 1 diabetes was historically fatal until the discovery of insulin (Banting et al., 1922). Even in the 21st century, insulin remains the primary treatment for T1D (Caroline, 2013). However, dosing insulin properly remains difficult for many T1D patients. Optimal blood glucose control requires mimicking the timing of body’s natural release patterns, such as basal release during the night, slow release between meals, and larger releases to control complex carbohydrates during mealtimes. Furthermore, the dosing must be altered for levels of physical activity, stress or other preexisting healthcare conditions (DiMeglio, 2018). Although various mechanisms of insulin delivery have been developed, such as intramuscular injections, aerosol insulin, and implanted insulin pumps, all of the methods have weaknesses (DiMeglio, 2018). Currently, the development of an artificial pancreas (combination of continuous glucose monitoring (GCM) device and implanted insulin pump) would provide the most promising method to control blood glucose levels (Kovatchev, 2017). Immune Therapy Since T1D is an autoimmune disorder, hope exists for an immune therapy that would prevent T-cell mediated attacks on β-cells. For example, the immunosuppressant ciclosporin temporarily inhibited T-cell activation, but it was unable to induce permanent disease remission (Feutren et al., 1986). Newer approaches have examined the efficacy of monoclonal antibodies that target either B-cell receptors (rituximab) or T-Cell receptors (teplizumab and otelixizumab), however these treatments failed to progress to stage three trials (DiMeglio, 2018). Future immunotherapies could be implemented during the early part of the disease process to slow the rate of β-cell mass (DiMeglio, 2018). Creating iPSC β-Cells for Treating Type 1 Diabetes Over the last decade, various stem cell therapies have gained attention as possible treatment for T1D. While there are many candidate types of stem cells, iPSCs have the capacity for selfrenewal, differentiation, and will not trigger an allogenic response (Leite et al., 2020). These factors make iPSCs an ideal candidate for creating β-cells for implantation. If successful, the implantation of iPSC derived β-cells would simultaneously lower blood glucose levels and avoid complications from allogeneic immune responses associated with cadaveric β-islets or human embryonic stem cells (ESCs). Of course, the new β-cells would be vulnerable to attack from the T1D patient’s immune system. However, since T1D is largely mediated by T-cells, the implanted β-cells could be protected in two different ways. First, the new β-cells could be genetically modified to reduce the expression of class 1 HLA, which has been correlated with T- cell activation (Leite et al., 2020). Alternatively, the implanted iPSC derived β-cells could be placed in a semipermeable device that permits the release of insulin, but prevents T-cells from contacting the β-cells, eliminating the need for immunosuppression (Leite et al., 2020; Ellis et al., 2017). The following sections outline the progress made towards an implantable, iPSC derived treatment for T1D. Cadaveric β-Islets Transplant + Immune Therapy Cadaveric β-islet implantation is an emerging treatment for advanced T1D, which must be coupled with immunosuppressants to prevent allogeneic immune responses (Shapiro et al., 2000; Sibley et al., 1985). The β-islets are surgically placed into the hepatic portal vein of the recipient. Strikingly, this procedure is low risk and can lead to high rates of insulin independence. However, due to the low availability of donors, and the complications from necessary immunosuppressants, the majority of T1D patients are not eligible for this islet transplantation despite the efficacy of the procedure (Shaprio et al., 2000, DiMeglio, 2018). However, cadaveric β-islet implantation set the stage for stem cell-based therapies, and the theoretical use of induced pluripotent stem cell (iPSC) derived β-cells may provide solutions to such limitations. Differentiation and Characteristics of iPSC Derived β-Cells The mere transplantation of pancreatic progenitor cells into mice can cause minor spontaneous differentiation into β-cells; however, specifically creating in vitro β-cells for transplantation is a far more efficient strategy to treat T1D. As reviewed by Millman & Pagliuca (2017) several successful protocols create functional β-cells from iPSCs (see Fig. 1). 2022-2023 C A T A L Y S T | 2 1
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